Compositions and Methods for Treating Anxiety and Compulsive Behavior

Abstract

Provided herein is compositions and methods for treating anxiety, obsession and/or pathologically compulsive behavior associated with various neuropsychiatric diseases.

1 . A compound of formula (I) or (II), or a pharmaceutically acceptable salt or prodrug thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 X 1 , X 2 , X 3 , and X 4  are each independently selected from: hydrogen; halo; hydroxyl; C 1-6  (e.g., C 1-3 ) alkoxyl optionally substituted with 1 or more hydroxyl, cyano and/or halo; C 1-6  (e.g., C 1-3 ) alkyl carbonyl; C 1-6  (e.g., C 1-3 ) alkoxycarbonyl; cyano; nitro; amine; R A  and R B ;
 wherein R A  at each occurrence is independently selected from C 1-6  (e.g., C 1-3 ) alkyl, C 2-6  (e.g., C 2-3 ) alkenyl and C 2-6  (e.g., C 2-3 ) alkynyl, each optionally substituted with 1 or more halo, hydroxyl, C 1-6  (e.g., C 1-3 ) alkoxyl, C 1-6  (e.g., C 1-3 ) thioalkoxyl, C 1-6  (e.g., C 1-3 ) alkyl carbonyl, C 1-6  (e.g., C 1-3 ) alkoxycarbonyl, cyano, nitro, and/or amine; 
 wherein R B  at each occurrence is independently selected from C 3-12  cycloalkyl, C 2-6  heterocyclyl, C 6-12  aryl and C 4-12  heteroaryl, each optionally substituted with 1 or more halo; hydroxyl; C 1-6  alkyl optionally substituted with 1 or more C 3-12  cycloalkyl, C 2-6  heterocyclyl, C 6-12  aryl, C 4-12  heteroaryl, amine, oxo, halo and/or hydroxyl; C 1-6  alkoxyl or C 1-6  thioalkoxyl, each optionally substituted with 1 or more C 3-12  cycloalkyl, C 2-6  heterocyclyl, C 6-12  aryl, C 4-12  heteroaryl, amine, oxo, halo and/or hydroxyl; C 1-6  (e.g., C 1-3 ) alkyl carbonyl optionally substituted with 1 or more C 3-12  cycloalkyl, C 2-6  heterocyclyl, C 6-12  aryl, C 4-12  heteroaryl, and/or amine; C 2-6  (e.g., C 2-3 ) alkoxycarbonyl; cyano; nitro; azide; amine; C 3-12  cycloalkyl; C 2-6  heterocyclyl; C 6-12  aryl; and/or C 4-12  heteroaryl; wherein each of the substituents C 3-12  cycloalkyl, C 2-6  heterocyclyl, C 6-12  aryl and C 4-12  heteroaryl is additionally optionally substituted with 1 or more halo, hydroxyl, C 1-6  alkyl, C 1-6  (e.g., C 1-3 ) alkoxyl, C 1-6  (e.g., C 1-3 ) thioalkoxyl, C 1-6  (e.g., C 1-3 ) alkoxycarbonyl, cyano, nitro and/or amine; 
 
 R 1  and R 2  at each occurrence, are each independently selected from C 1-12  alkyl, C 2-12  alkenyl or C 2-12  alkynyl, each optionally substituted with 1 or more C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, halo, hydroxyl, C 1-6  alkoxyl, C 1-6  thioalkoxyl, oxo, C 1-6  alkyl carbonyl, C 1-6  alkoxycarbonyl, cyano, nitro and/or amine; wherein the C 1-6  alkoxyl, C 1-6  thioalkoxyl, C 1-6  alkyl carbonyl, and C 1-6  alkoxycarbonyl groups each are optionally substituted with 1 or more C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, halo, hydroxyl, C 1-6  alkoxyl, C 1-6  thioalkoxyl, oxo, C 1-6  alkyl carbonyl, C 1-6  alkoxycarbonyl, cyano, nitro and/or amine; 
 Y is CH or N; and 
 n is an integral selected from 1-12. 
 
     
     
         2 . The compound or salt or prodrug of  claim 1 , wherein at least one of X 1 , X 2 , X 3 , and X 4  is not hydrogen. 
     
     
         3 . The compound or salt or prodrug of  claim 1 , wherein X 2  is not hydrogen. 
     
     
         4 . The compound or salt or prodrug of  claim 1 , selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         5 . The compound or salt or prodrug of any one of  claims 1 - 3 , wherein the compound is not 
       
         
           
           
               
               
           
         
       
     
     
         6 . The compound or salt or prodrug of any one of  claims 1 - 4 , for use in the treatment of anxiety disorder or a neuropsychiatric disease having an obsession and/or pathologically compulsive behavior component. 
     
     
         7 . The compound or salt or prodrug of  claim 5 , wherein the anxiety disorder or neuropsychiatric disease is selected from major depression, schizophrenia, autism, autism spectrum disorder, obsessive compulsive personality disorder, bipolar disorder, generalized anxiety disorder, social anxiety disorder, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), pediatric acute-onset neuropsychiatric syndrome (PANS), anorexia nervosa, bulimia nervosa, Tourette syndrome, Asperger syndrome, body dysmorphic disorder, eating disorders, panic disorder, social phobia, Sydenham's chorea, Parkinson's disease, Huntington's disease, hoarding disorder, tic disorder, trichotillomania, dementia, Alzheimer's disease, attention deficit hyperactivity disorder, dermatillomania, onychophagia, and drug addiction. 
     
     
         8 . The compound or salt or prodrug of any one of  claims 1 - 4  for use in the manufacture of a medicament for the treatment of anxiety disorder or a neuropsychiatric disease having an obsession and/or pathologically compulsive behavior component. 
     
     
         9 . The compound or salt or prodrug of any one of  claims 6 - 8 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         10 . A pharmaceutical composition comprising the compound or salt or prodrug of any one of  claims 1 - 5 , and a pharmaceutically acceptable carrier. 
     
     
         11 . A method for treating anxiety disorder or a neuropsychiatric disease having an obsession and/or pathologically compulsive behavior component, comprising administering an effective amount of a compound of formula (I) or (II) or a pharmaceutically acceptable salt or prodrug thereof, to a patient in need thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 X 1 , X 2 , X 3 , and X 4  are each independently selected from: hydrogen; halo; hydroxyl; C 1-6  (e.g., C 1-3 ) alkoxyl optionally substituted with 1 or more hydroxyl, cyano and/or halo; C 1-6  (e.g., C 1-3 ) alkyl carbonyl; C 1-6  (e.g., C 1-3 ) alkoxycarbonyl; cyano; nitro; amine; R A  and R B ;
 wherein R A  at each occurrence is independently selected from C 1-6  (e.g., C 1-3 ) alkyl, C 2-6  (e.g., C 2-3 ) alkenyl and C 2-6  (e.g., C 2-3 ) alkynyl, each optionally substituted with 1 or more halo, hydroxyl, C 1-6  (e.g., C 1-3 ) alkoxyl, C 1-6  (e.g., C 1-3 ) thioalkoxyl, C 1-6  (e.g., C 1-3 ) alkyl carbonyl, C 1-6  (e.g., C 1-3 ) alkoxycarbonyl, cyano, nitro, and/or amine; 
 wherein R B  at each occurrence is independently selected from C 3-12  cycloalkyl, C 2-6  heterocyclyl, C 6-12  aryl and C 4-12  heteroaryl, each optionally substituted with 1 or more halo; hydroxyl; C 1-6  alkyl optionally substituted with 1 or more C 3-12  cycloalkyl, C 2-6  heterocyclyl, C 6-12  aryl, C 4-12  heteroaryl, amine, oxo, halo and/or hydroxyl; C 1-6  alkoxyl or C 1-6  thioalkoxyl, each optionally substituted with 1 or more C 3-12  cycloalkyl, C 2-6  heterocyclyl, C 6-12  aryl, C 4-12  heteroaryl, amine, oxo, halo and/or hydroxyl; C 1-6  (e.g., C 1-3 ) alkyl carbonyl optionally substituted with 1 or more C 3-12  cycloalkyl, C 2-6  heterocyclyl, C 6-12  aryl, C 4-12  heteroaryl, and/or amine; C 2-6  (e.g., C 2-3 ) alkoxycarbonyl; cyano; nitro; azide; amine; C 3-12  cycloalkyl; C 2-6  heterocyclyl; C 6-12  aryl; and/or C 4-12  heteroaryl; wherein each of the substituents C 3-12  cycloalkyl, C 2-6  heterocyclyl, C 6-12  aryl and C 4-12  heteroaryl is additionally optionally substituted with 1 or more halo, hydroxyl, C 1-6  alkyl, C 1-6  (e.g., C 1-3 ) alkoxyl, C 1-6  (e.g., C 1-3 ) thioalkoxyl, C 1-6  (e.g., C 1-3 ) alkoxycarbonyl, cyano, nitro and/or amine; 
 
 R 1  and R 2  at each occurrence, are each independently selected from C 1-12  alkyl, C 2-12  alkenyl or C 2-12  alkynyl, each optionally substituted with 1 or more C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, halo, hydroxyl, C 1-6  alkoxyl, C 1-6  thioalkoxyl, oxo, C 1-6  alkyl carbonyl, C 1-6 alkoxycarbonyl, cyano, nitro and/or amine; wherein the C 1-6  alkoxyl, C 1-6  thioalkoxyl, C 1-6  alkyl carbonyl, and C 1-6  alkoxycarbonyl groups each are optionally substituted with 1 or more C 1-6  alkyl, C 2-6  alkenyl, C 2-6  alkynyl, halo, hydroxyl, C 1-6  alkoxyl, C 1-6  thioalkoxyl, oxo, C 1-6  alkyl carbonyl, C 1-6 alkoxycarbonyl, cyano, nitro and/or amine; 
 Y is CH or N; and 
 n is an integral selected from 1-12. 
 
     
     
         12 . The method of  claim 11 , wherein at least one of X 1 , X 2 , X 3 , and X 4  is not hydrogen. 
     
     
         13 . The method of  claim 11 , wherein X 2  is not hydrogen. 
     
     
         14 . The method of  claim 11 , wherein the compound is selected from: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         15 . The method of any one of  claims 11 - 13 , wherein the compound is 
       
         
           
           
               
               
           
         
       
     
     
         16 . The method of any one of  claims 11 - 15 , wherein the anxiety disorder or neuropsychiatric disease is selected from major depression, schizophrenia, autism, autism spectrum disorder, obsessive compulsive personality disorder, bipolar disorder, generalized anxiety disorder, social anxiety disorder, pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS), pediatric acute-onset neuropsychiatric syndrome (PANS), anorexia nervosa, bulimia nervosa, Tourette syndrome, Asperger syndrome, body dysmorphic disorder, eating disorders, panic disorder, social phobia, Sydenham's chorea, Parkinson's disease, Huntington's disease, hoarding disorder, tic disorder, trichotillomania, dementia, Alzheimer's disease, attention deficit hyperactivity disorder, dermatillomania, onychophagia, and drug addiction.